Synthetic method of 4-isothiocyanato-2-(trifluoromethyl) benzonitrile

A technology of trifluoromethyl and isothiocyanate, which is applied in the field of synthesis of pharmaceutical intermediates to achieve the effect of high product yield and low price

Inactive Publication Date: 2017-11-28
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The object of the present invention is to overcome the various problems that exist in the synthetic technique of existing pharmaceutical intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and provide a kind of new synthetic method

Method used

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  • Synthetic method of 4-isothiocyanato-2-(trifluoromethyl) benzonitrile

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Effect test

Embodiment 1

[0029] The synthetic method of 4-isothiocyanate-2-(trifluoromethyl) benzonitrile comprises the following steps:

[0030] a. Dissolve 3-trifluoromethyl-4-cyanoaniline (Compound I) (1.12g, 6mmol, 1.0eq) and phenyl thiochloroformate (1.04g, 6mmol, 1.0eq) in 20mL of dichloromethane , Stirring was started at about 25°C, and the reaction was complete after 2 hours. After filtration, the insoluble matter was removed, the filtrate was collected, and the solvent was removed under reduced pressure to obtain a yellow solid (II).

[0031] b. Weigh the yellow solid (II) (0.64 g, 2 mmol), dissolve it in 20 mL of toluene, heat up and stir to reflux, and keep for 18 h. The insoluble matter in the reaction solution was filtered off, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. After column chromatography, 274 mg of the target product 4-isothiocyanate-2-(trifluoromethyl)benzonitrile was obtained, with a yield of 60.1%.

[0032] Target product 4...

Embodiment 2

[0036] The synthetic method of 4-isothiocyanate-2-(trifluoromethyl) benzonitrile comprises the following steps:

[0037] a. Dissolve 3-trifluoromethyl-4-cyanoaniline (Compound I) (1.12g, 6mmol, 1.0eq) and phenyl thiochloroformate (0.69g, 4mmol, 0.67eq) in 20mL of dichloromethane , Stirring was started at about 25°C, and the reaction was complete after 2 hours. After filtration, the insoluble matter was removed, the filtrate was collected, and the solvent was removed under reduced pressure to obtain a yellow solid (II).

[0038] b. Weigh the yellow solid (II) (0.64 g, 2 mmol), dissolve it in 20 mL of toluene, heat up and stir to reflux, and keep for 18 h. The insoluble matter in the reaction solution was filtered off, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. After column chromatography, 330 mg of the target product 4-isothiocyanate-2-(trifluoromethyl)benzonitrile was obtained, with a yield of 72.3%.

[0039] The target prod...

Embodiment 3

[0043] The synthetic method of 4-isothiocyanate-2-(trifluoromethyl) benzonitrile comprises the following steps:

[0044] a. Dissolve 3-trifluoromethyl-4-cyanoaniline (Compound I) (1.12g, 6mmol, 1.0eq) and phenyl thiochloroformate (0.52g, 3mmol, 0.52eq) in 20mL of dichloromethane , Stirring was started at about 25°C, the reaction was complete after 2 hours, filtered to remove insoluble matter, the filtrate was collected, and the solvent was removed under reduced pressure to obtain a yellow solid (II).

[0045] b. Weigh the yellow solid (II) (0.64 g, 2 mmol), dissolve it in 20 mL of toluene, heat up and stir to reflux, and keep for 18 h. The insoluble matter in the reaction solution was filtered off, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. After column chromatography, 361 mg of the target product 4-isothiocyanate-2-(trifluoromethyl)benzonitrile was obtained, with a yield of 79.0%.

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Abstract

The invention discloses a method for synthesizing 4-isothiocyano-2-(trifluoromethyl)benzonitrile. The method is divided into the following two steps: step 1, using 3-trifluoromethyl-4-cyano Aniline (I) is the starting material, reacts with phenyl thiochloroformate in organic solvents such as dichloromethane to obtain intermediate (II); step 2, intermediate (II) reflux reaction in toluene to remove a molecule Phenol obtains formula (III) product 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and the reaction formula is as follows: the inventive method has low cost, safety and environmental protection, simple and easy operation, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for synthesizing the key intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile of the anti-prostate cancer drug enzalutamide. Background technique [0002] 4-Isothiocyanato-2-(trifluoromethyl)benzonitrile belongs to isothiocyanate compounds and is a key intermediate in the synthesis of the anti-prostate cancer drug enzalutamide. Its chemical synthesis generally uses 3-trifluoromethyl-4-cyanoaniline as the starting material. Because it contains strong electron-withdrawing groups such as trifluoromethyl and cyano, it is relatively inert and makes it difficult to synthesize the target product. At present, the synthesis methods reported in the literature mainly include the following three types. [0003] Method 1: Sawyers, Jung et al. (see WO2006124118A1) used 3-trifluoromethyl-4-cyanoaniline as a raw material, reacted with thiophos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C331/28C07C333/08
CPCC07C331/28C07C333/08
Inventor 胡学雷冯菊红曾令康葛燕丽
Owner WUHAN INSTITUTE OF TECHNOLOGY
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